rs193922433
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong
The NM_000388.4(CASR):c.2243C>A(p.Pro748Gln) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P748R) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CASR
NM_000388.4 missense
NM_000388.4 missense
Scores
11
2
1
Clinical Significance
Conservation
PhyloP100: 7.90
Genes affected
CASR (HGNC:1514): (calcium sensing receptor) The protein encoded by this gene is a plasma membrane G protein-coupled receptor that senses small changes in circulating calcium concentration. The encoded protein couples this information to intracellular signaling pathways that modify parathyroid hormone secretion or renal cation handling, and thus this protein plays an essential role in maintaining mineral ion homeostasis. Mutations in this gene are a cause of familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
?
In a topological_domain Extracellular (size 23) in uniprot entity CASR_HUMAN there are 14 pathogenic changes around while only 3 benign (82%) in NM_000388.4
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr3-122284197-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 936871.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=2, Uncertain_significance=1}.
PP2
?
Missense variant where missense usually causes diseases, CASR
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
?
Variant 3-122284197-C-A is Pathogenic according to our data. Variant chr3-122284197-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122284197-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.2243C>A | p.Pro748Gln | missense_variant | 7/7 | ENST00000639785.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.2243C>A | p.Pro748Gln | missense_variant | 7/7 | 1 | NM_000388.4 | P1 | |
CASR | ENST00000498619.4 | c.2273C>A | p.Pro758Gln | missense_variant | 7/7 | 1 | |||
CASR | ENST00000638421.1 | c.2243C>A | p.Pro748Gln | missense_variant | 7/7 | 5 | P1 | ||
CASR | ENST00000490131.7 | c.2012C>A | p.Pro671Gln | missense_variant | 5/5 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461402Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727016
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
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0
AN:
1461402
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Cov.:
33
AF XY:
AC XY:
0
AN XY:
727016
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
EpiCase
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EpiControl
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial hypocalciuric hypercalcemia Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 19, 2023 | Variant summary: CASR c.2243C>A (p.Pro748Gln) results in a non-conservative amino acid change located in the GPCR family 3, C-terminal domain (IPR017978) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. A discrepancy between the genome and transcript sequences at the adjacent position c.2244 of this codon results in the minor allele, namely "C" at this location. As majority of occurrences have a "C" at this location, this variant can also be annotated as c.2243_2244delinsAC or as c.2243C>A, both of which encode p.Pro748His. A different variant, c.2243C>G (p.Pro748Arg) at the same location has been classified as pathogenic, supporting the critical relevance of this residue to protein function. The variant was absent in 250560 control chromosomes. c.2243C>A encoding p.Pro748His, has been reported in the literature in heterozygous individuals affected with Familial Hypocalciuric Hypercalcemia (e.g. Mouly_2020, Cetani_2009). To our knowledge, no reports of this variant encoding p.Pro748Gln have been reported in the literature. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact of p.Pro748His on protein function. The most pronounced variant effect results in >50%-90% of normal activity (e.g.Cetani_2009). The following publications have been ascertained in the context of this evaluation (PMID: 32347971, 19073830). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2017 | The P748H variant has been published previously in association with familial hypocalciuric hypercalcemia (Cetani et al. 2009). It is reported as likely pathogenic in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000052090.1; Landrum et al., 2015). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). P748H is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, functional studies have shown the P748H receptor shows a reduced response to calcium in comparison to wild type (Cetani et al. 2009). In summary, this variant is likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Polyphen
D;D;.;.
Vest4
0.87
MutPred
0.92
.;.;Loss of catalytic residue at P757 (P = 0.0101);.;
MVP
1.0
MPC
1.5
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at